The pharmacokinetic properties of darunavir, is used in combination with ritonavir, have been studied in healthy volunteers and in patients. Concentra-tion of darunavir in plasma was higher in patients infected with than in healthy people. This difference can be explained by higher concentrations of alpha-1-acid glycoprotein in patients infected with , which leads to increased amounts of darunavir associated with alpha-1-acid glycoprotein plasma. Darunavir is metabolised mainly isoenzyme. Ritonavir inhibitsmasteron enanthate isozyme liver and thus considerably increases the plasma concentration of darunavir.
After ingestion darunavir rapidly absorbed in the gastrointestinal tract. Maximum plasma concentration of darunavir in the presence of low doses of ritonavir is reached after 2.5 -. 4.0 parts per dose The absolute bioavailability of darunavir (600 mg) at intake was approximately 37% and increased up to about 82% in the presence of ritonavir (100 mg of two times a day). The total effect of ritonavir on the bioavailability of darunavir consisted of approximately 14-fold increase darunavir plasma concentrations after a single oral administration of 600 mg of darunavir in combination with ritonavir (100 mg twice daily).
When taken on an empty stomach the relative bioavailability of darunavir in the presence of low dose ritonavir was 30% lower than when eating. Consequently, drug should be taken with ritonavir with food. The nature of the food did not affect the plasma concentrations of darunavir.
Darunavir about 95% bound to plasma proteins, mainly alpha-1-acid glycoprotein.
In experiments in vitro on human liver microsomes showed that exposed predominantly darunavir oxidative metabolism. Darunavir is metabolized primarily in the liver by cytochrome P450 system, almost exclusively isoenzyme CYP3A4. A study in which healthy volunteers received 14 C-darunavir showed that most of the radioactivity in plasma after a single administration of 400 mg of darunavir and ritonavir 100 mg accounted for by unchanged darunavir. The man identified at least 3 oxidative metabolites of darunavir; Activity of these metabolites against wild-type HIV was less than 1/10 the activity masteron enanthate of darunavir.
After a single dose of 400 mg 14C-darunavir and ritonavir 100 mg of approximately 79.5% and 13.9% of the radioactivity was detected in the feces and urine, respectively. The share unchanged darunavir accounted for approximately 41.2% and 7.7% of the radioactivity in faeces and urine, respectively. The final half-life of darunavir was approximately 15 hours when it is received in combination with ritonavir.Darunavir clearance following intravenous administration of 150 mg was 32.8 l / h (without ritonavir) and 5.91 l / h in the presence of low doses of ritonavir.
Special patient groups
The pharmacokinetics of darunavir in combination with ritonavir in children aged 6 to 18 years of age and weighing at least 20 kg is comparable to the pharmacokinetics in adult patients receiving the combination of / ritonavir 600/100 mg 2 times a day.
The pharmacokinetics of darunavir in combination with ritonavir in children aged 3 to 6 years old and weighing between 10 kg to 20 kg is comparable to the pharmacokinetics in adult patients receiving the combination of / ritonavir 600/100 mg 2 times a day.
Population pharmacokinetic analysis in HIV infected patients showed no significant differences in the pharmacokinetic parameters of darunavir in the age group 18 – 75 years (in the analysis of 12 HIV-infected patients aged 65 years and older were included).
Population pharmacokinetic analysis revealed slightly higher (16.8%) of the concentration of darunavir in HIV-positive women than in HIV-infected men. This difference is not clinically significant.
Patients with impaired renal function
Results of the study with 14C-darunavir with ritonavir showed that approximately 7.7% of the administered dose of darunavir excreted in the urine in unchanged form. Patients with impaired renal function, the pharmacokinetics of darunavir has not studied, but a population pharmacokinetic analysis showed no significant changes in pharmacokinetic parameters of darunavir in HIV-infected patients with moderate to severe renal function impairment (creatinine clearance of serum 30-60 ml / min, n = 20).
Patients with impaired hepatic function
Darunavir is primarily metabolised and excreted by the liver. In masteron enanthate a study using multiple doses of in combination with ritonavir (600/100 mg) twice a day has been shown that stable pharmacokinetic parameters of darunavir in patients with mild (Class A according to Child-Pugh, n = 8) and moderate violation liver function (class B Child-Pugh, n = 8) were comparable with those parameters in healthy individuals. The effect of severe hepatic impairment on the pharmacokinetics of darunavir has not been studied.
Treatment of HIV infection in adults patients (in combination with low dose ritonavir and other antiretroviral agents).